title: Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration.
abstract: Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARα (dnRARα) showed markedly diminished lethality. The dnRARα transgenic T cells showed reduced Th1 differentiation and α4β7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.
authors.affiliation: University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, Minneapolis, MN;
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Aoyama
authors.forename: Asim
authors.initials: A
authors.lastname: Saha
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Riddle
authors.forename: Rachelle G
authors.initials: RG
authors.lastname: Veenstra
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Rune
authors.initials: R
authors.lastname: Blomhoff
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Leshara M
authors.initials: LM
authors.lastname: Fulton
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.forename: Roshantha A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Guo
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002454:Cell Differentiation / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D007422:Intestines / Q000276:immunology*; D051379:Mice; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000607072:Rara protein, mouse; D016201:Receptors, Lymphocyte Homing; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin